An ion cyclotron resonance spectrometer (FT/ICR) with an external atmospheric pressure electrospray ionization source was used for the analysis of picomolar quantities of proteins or unknown biological compounds in aqueous solutions. The performance of this instrumentation was improved by a computer modeling ion optic study of quadrupolar axialization as a means of collecting ions in the center of the ICR cell. An unbalanced mode of quadrupolar axialization was proposed, implemented, and demonstrated to significantly improve performance over a broad mass range. A new desorption ionization technique, massive cluster impact ionization, was tested in combination with liquid chromatography-particle beam transport on a quadrupole mass spectrometer. This desorption ionization differs from fast atom bombardment in that dried particles can be desorbed and ionized without an organic matrix, facilitating the detection of organic compounds directly deposited on a flat surface by the particle beam interface. Studies with repetitive flow injections of acetylcholine and gramicidin S were performed to demonstrate the feasibility of this technique. Derivatization reagents for improved detection of alcohols and amino acids by negative chemical ionization mass spectrometry were tested (anthraquinone-2-carbonyl chloride, pentafluorobenzyl chloroformate). The pentafluorobenzyl carbamate-ethyl esters of amino acids are particularly favorable derivatives, readily formed in aqueous solutions at trace concentrations, and exhibit excellent chromatographic and mass spectrometric properties.